JP2012036208A - Aqueous liquid agent for topical use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an aqueous liquid agent for topical use having excellent anti-inflammatory action and anti-pruritic action.SOLUTION: The aqueous liquid agent for topical use contains pranoprofen or its pharmacologically permissible salt and an antiallergic agent selected from antihistamic agent and a mediator isolation suppressing agent.

Description

  The present invention relates to an aqueous topical solution excellent in anti-inflammatory action and antipruritic action, comprising pranoprofen or a pharmacologically acceptable salt thereof and an antiallergic agent selected from an antihistamine and a mediator release inhibitor. About.

  Antihistamines that block the binding of released histamine to receptors are used as inhibitors or antipruritic agents for allergic reactions, and mediator release inhibitors are used as eye drops and nasal drops as preventive agents for allergic inflammation. . However, allergic conjunctivitis caused by pollen may scratch the eyes due to itching and cause inflammation of the ocular mucosa. In addition, allergic symptoms caused by ticks may cause blepharoconjunctivitis that causes red eyelids. Furthermore, corneal epithelial disorder is strongly observed in spring catarrh, causing diffuse superficial keratitis. In such a case, for example, if an eye drop (or nasal drop) for anti-inflammation and an eye drop (or nasal drop) for anti-allergy are used in combination, the both drugs are diluted. It may happen that the effective medicinal effect cannot be exhibited. For this reason, the development of a topical aqueous solution having an antipruritic action and an anti-inflammatory action is desired.

  An object of the present invention is to provide a topical aqueous liquid preparation that exhibits an antipruritic effect and is excellent in anti-inflammatory action.

As a result of intensive research to achieve the above object, the present inventor has found that pranoprofen (chemical name: α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7acetic acid) or a drug thereof. The inventors have found that inflammatory symptoms and itching can be drastically improved by adding an antiallergic agent selected from an antihistamine and a mediator release inhibitor to a physically acceptable salt, and the present invention has been completed.
That is, the present invention
(1) A topical ocular mucosa or nasal mucosa characterized by containing pranoprofen or a pharmacologically acceptable salt thereof and at least one antiallergic agent selected from an antihistamine and a mediator release inhibitor. Aqueous liquid,
(2) Planoprofen or a pharmacologically acceptable salt thereof is pranoprofen, the lower limit is 0.005 w / v%, the upper limit is 2.0 w / v%, and the antiallergic agent is lower than 0. 001 w / v%, an aqueous topical solution according to the above (1), which is contained in a concentration range having an upper limit of 5 w / v%,
(3) The topical aqueous liquid preparation according to (1) or (2), wherein the antiallergic agent is an antihistamine,
(4) An aqueous topical solution according to (3) above, which contains an antihistamine in a concentration range with a lower limit of 0.001 w / v% and an upper limit of 1 w / v%,
(5) The topical aqueous solution according to (4) above, wherein the antihistamine is chlorpheniramine, diphenhydramine, or a salt thereof,
(6) The topical aqueous solution according to (5) above, wherein the antihistamine is chlorpheniramine maleate or diphenhydramine hydrochloride,
(7) The aqueous topical solution according to the above (1) or (2), wherein the antiallergic agent is a mediator release inhibitor,
(8) A topical aqueous liquid preparation according to the above (7) containing a mediator release inhibitor in a concentration range having a lower limit of 0.005 w / v% and an upper limit of 5 w / v%,
(9) The topical aqueous solution according to (8) above, wherein the mediator release inhibitor is cromoglycic acid or a salt thereof, and (10) the above (1) to (9), which is an eye drop, eye wash or nasal drop Of the topical aqueous solution.

  An aqueous topical solution containing pranoprofen of the present invention or a pharmacologically acceptable salt thereof and an antiallergic agent selected from an antihistamine and a mediator release inhibitor suppresses inflammation such as edema and itching It can also be advantageously used to suppress this.

  Examples of the topical aqueous liquid preparation of the present invention include aqueous solutions, suspensions, and emulsions, with aqueous solutions being preferred. In the present invention, pranoprofen pharmacologically acceptable salts include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, organic bases such as triethylamine, diethylamine, morpholine, piperazine and the like. However, it is not limited to these. In the topical aqueous liquid preparation of the present invention, the content of pranoprofen or a pharmacologically acceptable salt thereof is usually about 0.005 w / v%, preferably 0.01 w / v, as pranoprofen. %, More preferably about 0.05 w / v%, the upper limit is about 2.0 w / v%, preferably about 1.0 w / v%, more preferably about 0.5 w / v%, still more preferably 0.1 w / V%, and increase / decrease appropriately according to the purpose of use and the degree of inflammation. The anti-allergic agent applied to the topical aqueous solution of the present invention mainly refers to a drug having an antihistamine action (antihistamine) and a drug having a suppressive action on release of a chemical transmitter from mast cells (mediator release inhibitor). However, drugs having both actions are naturally included. Here, the antihistaminic action is an action that competitively antagonizes histamine at the histamine receptor, and the mediator release inhibitory action is an action of suppressing release of chemical mediators such as histamine and SRS-A from mast cells due to allergic reaction. Say. Antihistamines applied to the topical aqueous solution of the present invention include chlorpheniramine maleate, chlorpheniramine d-maleate, diphenhydramine, diphenhydramine hydrochloride, cyproheptadine hydrochloride, iproheptin hydrochloride, hydroxyzine hydrochloride, hydroxyzine pamoate, hydrochloric acid Promethazine, homochlorocyclidine hydrochloride, alimemazine tartrate, clemastine fumarate, mequitazine and the like may be mentioned, but these may be used alone or in combination of two or more. Preferred are chlorpheniramine maleate and diphenhydramine hydrochloride. The concentration of the antihistamine may be appropriately determined depending on various properties of each drug, but is usually about 0.001 w / v%, preferably about 0.003 w / v%, more preferably about 0.005 w / v%. The upper limit is about 1 w / v%, preferably about 0.5 w / v%. In the case of eye drops, a lower limit of about 0.01 w / v% and an upper limit of about 0.05 w / v% are particularly preferable. Examples of the mediator release inhibitor applied to the topical aqueous solution of the present invention include ketotifen, azelastine, oxatomide, cromoglycic acid and its salts (sodium salt, etc.), tranilast, amlexanox, etc., preferably sodium cromoglycate It is. The concentration of the mediator release inhibitor is usually about 0.005 w / v% lower limit, preferably about 0.01 w / v%, about 5 w / v% upper limit, preferably about 2 w / v%.

  For the topical aqueous liquid preparation of the present invention, pharmaceutically acceptable additives such as buffering agents, tonicity agents, solubilizing agents, preservatives, viscous bases, chelating agents, cooling agents and the like are appropriately selected. Can be added.

  Examples of the buffer include a phosphate buffer, a borate buffer, a citrate buffer, a tartrate buffer, an acetate buffer, and an amino acid. Examples of the isotonic agent include saccharides such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin and propylene glycol, salts such as sodium chloride, boric acid and the like. Examples of the solubilizer include polyoxyethylene sorbitan monooleate (for example, polysorbate 80), nonionic surfactants such as polyoxyethylene hydrogenated castor oil, tyloxapol, and pluronic, and polyhydric alcohols such as glycerin and macrogol. It is done. Examples of the preservative include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, paraoxybenzoic acid such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate. Examples thereof include esters, benzyl alcohol, sorbic acid and salts thereof (sodium salt, potassium salt, etc.), thimerosal, chlorobutanol, sodium dehydroacetate and the like. Examples of the viscous base include water-soluble polymers such as polyvinyl pyrrolidone, polyethylene glycol, and polyvinyl alcohol, and celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. Examples of the chelating agent include sodium edetate and citric acid, and examples of the cooling agent include l-menthol, borneol, camphor, and eucalyptus oil.

  The pH of the topical aqueous solution of the present invention is usually adjusted to about 5.0 to about 8.5, preferably about 6.0 to about 8.0.

  In the topical aqueous solution of the present invention, if necessary, a vasoconstrictor such as naphazoline and its salts (hydrochloride, nitrate), tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine and its hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, Anti-inflammatory agents such as dipotassium glycyrrhizinate, allantoin, epsilon aminocaproic acid, vitamins such as flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, tocopherol acetate, amino acids such as aspartic acid and aminoethyl sulfonic acid, and neostigmine methyl sulfate You may mix | blend an anticholinesterase agent etc.

  The topical aqueous liquid preparation of the present invention can be produced by a preparation method known per se, for example, the method described in the 14th revised Japanese Pharmacopoeia, General Preparation Liquid or Eye Drops.

  The topical aqueous solution of the present invention is used locally as an eye drop, eye wash, or nose drop on the ocular or nasal mucosa of a warm-blooded animal (eg, human, rat, mouse, rabbit, cow, pig, dog, cat, etc.). To be administered. When used as an eye drop, it can be used even when a contact lens such as a non-oxygen permeable hard contact lens, an oxygen permeable hard contact lens, or a soft contact lens is worn. When the topical aqueous solution of the present invention is used as an eye drop for adults with blepharing conjunctivitis, allergic conjunctivitis, spring catarrh, blepharitis, keratitis, etc. An ophthalmic solution containing 0.03 w / v% chlorpheniramine and / or 0.01 w / v% sodium cromoglycate may be instilled 1 to 2 drops 3 to 6 times a day. The number of times can be appropriately increased or decreased depending on the degree of symptoms.

  Hereinafter, the present invention will be specifically described with reference to experimental examples and examples, but the present invention is not limited thereto.

Experimental Example 1 Effects of Pranoprofen and Antihistamine-Containing Eye Drops on Rat Carrageenan Edema Eye drops A to E having the formulations shown in Table 1 below were prepared by a conventional method. Under anesthesia, 50 μL of 1% carrageenan solution was injected into the rat upper eyelid conjunctiva to induce conjunctival edema. To clarify the edema site, 2.5 mL / kg of 1% Evans blue solution was injected from the tail vein immediately after the carrageenin injection. 5 μL of each eye drop was instilled 15 minutes before, 30 minutes before and 120 minutes after the carrageenin injection (n = 6). As a control group, physiological saline was instilled in the same manner. Rats were euthanized 4 hours after the carrageenin injection, and after removing the blue-stained conjunctival edema site (hereinafter also simply referred to as the conjunctiva) of the upper eyelid conjunctiva, the wet weight was immediately measured, and the inhibition rate was calculated according to the following formula. .
Inhibition rate (%) = (1−X / C) × 100
Here, X represents the conjunctival wet weight average value of the eye drop administration group, and C represents the conjunctival wet weight average value of the control (saline solution administration) group.

  The results of the conjunctival wet weight average value and the inhibition rate are shown in Table 2. Inhibition rates of 0.1 w / v% pranoprofen (formulation D) and 0.06 w / v% chlorpheniramine maleate (formulation E) alone instilled were 42.1% and 27.5%, respectively. It was. On the other hand, the inhibition rate of the eye drop (prescription A) containing half of the amount of pranoprofen (0.05 w / v%) and chlorpheniramine maleate (0.03 w / v%) was 56.4%, Excellent effect on arachidonic acid-induced conjunctival edema.

Experimental Example 2 Effects of Eye Drops Containing Planoprofen and Mediator Release Inhibitor on Rat Carrageenan Edema Eye drops FG having the formulations shown in Table 3 below were prepared by a conventional method. The inhibition rate was calculated in the same manner as in Experimental Example 1 (n = 6).

The results of the conjunctival wet weight average value and the inhibition rate are shown in Table 4.
Inhibition rates of 0.05 w / v% pranoprofen (formulation G) and 0.1 w / v% sodium cromoglycate (formulation H) alone instillation groups were 25.1% and 17.0%, respectively. On the other hand, the ophthalmic solution (formulation F) containing pranoprofen (0.05 w / v%) and sodium cromoglycate (0.01 w / v%) had an inhibition rate of 41.2%, and arachidonic acid-induced conjunctival edema It showed an excellent effect.

Example 1
In accordance with a conventional method, eye drops were prepared according to the following formulation.
Planoprofen 0.05g
Chlorpheniramine maleate 0.05g
Boric acid 1.6g
Borax appropriate amount benzalkonium chloride 0.005g
Polysorbate 80 0.1g
Sterile purified water 100ml
pH 7.5

Example 2
In accordance with a conventional method, eye drops were prepared according to the following formulation.
Planoprofen 0.05g
Diphenhydramine hydrochloride 0.05g
Sodium dihydrogen phosphate 0.2g
Sodium chloride 0.8g
Benzalkonium chloride 0.005g
Polysorbate 80 0.1g
Sodium hydroxide appropriate amount sterilized purified water total amount 100ml
pH 7.5

Example 3
According to a conventional method, a nasal drop was prepared according to the following formulation.
Planoprofen 0.05g
Chlorpheniramine maleate 0.5g
Boric acid 1.6g
Borax appropriate amount benzalkonium chloride 0.005g
Polysorbate 80 0.1g
Sterile purified water 100ml
pH 7.5

Example 4
According to a conventional method, an eye wash was prepared according to the following formulation.
Planoprofen sodium salt 0.005g
Chlorpheniramine maleate 0.006g
Boric acid 1.6g
Borax appropriate amount benzalkonium chloride 0.005g
Polysorbate 80 0.1g
l-Menthol 0.004g
Sterile purified water 100ml
pH 7.0

Example 5
In accordance with a conventional method, eye drops were prepared according to the following formulation.
Planoprofen 0.05g
Chlorpheniramine maleate 0.03g
Cromoglycate sodium 0.1g
Boric acid 1.6g
Borax appropriate amount benzalkonium chloride 0.005g
Polysorbate 80 0.1g
Sterile purified water 100ml
pH 7.5

Example 6
In accordance with a conventional method, eye drops were prepared according to the following formulation.
Planoprofen 0.05g
Chlorpheniramine maleate 0.03g
Boric acid 1.6g
Borax appropriate amount benzalkonium chloride 0.005g
Polysorbate 80 0.1g
Sterile purified water 100ml
pH 7.5

Example 7
In accordance with a conventional method, eye drops were prepared according to the following formulation.
Planoprofen 0.05g
Chlorpheniramine maleate 0.03g
Cromoglycate sodium 0.1g
Boric acid 1.6g
Borax appropriate amount benzalkonium chloride 0.005g
Polysorbate 80 0.1g
l-Menthol 0.005g
Canful 0.001g
Borneol 0.001g
Sterile purified water 100ml
pH 7.5

Example 8
In accordance with a conventional method, eye drops were prepared according to the following formulation.
Planoprofen 0.05g
Chlorpheniramine maleate 0.03g
Boric acid 1.6g
Borax appropriate amount potassium sorbate 0.1g
Polysorbate 80 0.1g
l-Menthol 0.005g
Sterile purified water 100ml
pH 7.5

Claims (5)

  An aqueous liquid for topical ophthalmic or nasal mucosa characterized by containing pranoprofen or a pharmacologically acceptable salt thereof and a mediator release inhibitor.   Planoprofen or a pharmacologically acceptable salt thereof is pranoprofen, the lower limit is 0.005 w / v%, the upper limit is 2.0 w / v%, and the mediator release inhibitor is 0.001 w / v. The topical aqueous liquid preparation according to claim 1, which is contained in a concentration range of v%, the upper limit being 5 w / v%.   The topical aqueous liquid preparation according to claim 2, comprising a mediator release inhibitor in a concentration range having a lower limit of 0.005 w / v% and an upper limit of 5 w / v%.   The topical aqueous liquid preparation according to any one of claims 1 to 3, wherein the mediator release inhibitor is cromoglycic acid or a salt thereof.   The topical aqueous liquid preparation according to any one of claims 1 to 4, which is an eye drop, an eye wash or a nasal drop.